Many biologically active polyunsaturated fatty acids have one or more carbon-carbon double bonds in the cis configuration. Free radicals have been reported to support isomerization of these bonds to a less desirable trans configuration. Cis/trans isomerization can adversely effect polyunsaturated compounds intended for pharmaceutical use, for example, by reducing biological activity, and/or complicating synthesis. See, for example, C. Ferreri et al. (2007) Mol. Biotech. 37:19; Chatgilialoglu, C et al. (2002) Free Rrad. Biology & Medicine, 33: 1681; and WO 2002/100991.
Some, but not all, free radicals have been reported to support cis/trans isomerism of particular polyunsaturated compounds. It is believed that the kinetics of radical-mediated oxidation depend on several parameters including the chemical nature of the unsaturated compound to be made, temperature, pH, presence or absence of light, oxygen, etc. Free radicals have been reported to occur naturally in the environment or as unwanted by-products that are produced from certain chemical reactions. See, for example, Mengele, E. A et al. (2010) Mos. Univ. Chemistry Bull 65: 210.
There have been attempts to reduce oxidation and cis/trans isomerism of carbon-carbon double bonds. In one approach, an antioxidant such as octyl gallate, ascorbic acid, a polyphenol, mercaptoethanol, beta-carotene, or 2,6,-di-tert-butyl-4-methylphenol (BHT), for example, is added to reduce unwanted oxidation reactions. See Mengele, E. A, ibid; Klein, E and N. Weber (2001) J. Agric. Food Chem. 49: 1224; and Hung, W-L, et al. (2011) J. Agric. Food Chem. 1968.
There have been reports that certain polyunsaturated trifluoromethyl ketone compounds have useful biological activities. See, for example, U.S. Pat. No. 7,687,543; Huwiler, A et al. (2012) Br. J. Pharm. 167: 1691.
Methods for preparing particular polyunsaturated ketones have been disclosed. In one method disclosing the synthesis of particular polyunsaturated trifluoromethyl ketones, a Mitsunobu-type reaction was used to transform an alcohol to the corresponding thioester. Further chemical reactions were said to produce the polyunsaturated trifluoromethyl ketone (compound 18 therein) in 71% yield. See Holmeide, A and L. Skattebol (2000) J. Chem. Soc. Perkin Trans. 1: 2271.
There is general recognition that a compound intended for pharmaceutical use should be produced in high yield, e.g. 70% or more. Less than satisfactory yields can be associated with unwanted side products. These can be costly or difficult to remove from the main product (API), thereby making further pharmaceutical development difficult. Additionally, regulatory agencies often require a detailed analysis of side products in compounds intended for pharmaceutical use. This requirement can make scale-up costs prohibitive.
The Mitsunobu reaction is reported to involve the addition of a new functional group, often an ester, to a primary or secondary alcohol using, among other reagents, a phosphine and an azodicarboxylate. The mechanism of reaction is reported to be complex and there is controversy about the identity of the reaction intermediates. See, for example, But, T and P. Toy (2007) Chem. Asian J. 2: 1340; and Swamy, K. C et al. (2009) Chem. Rev. 109: 2551. This makes the outcome of certain Mitsonobu reactions difficult to predict.
In many instances, a Mitsunobu reaction is conducted by mixing the alcohol, carboxylic acid reactant and phosphine together in solvent at low temperature. Next, the azodicarboxylate is usually added and the reaction stirred for several hours to allow the carboxylic acid to react with the alcohol to form an ester. The present inventors have found that this process gives impurities in the context of the polyunsaturated compounds of the invention. For example, this reaction order often leads to unwanted oxidation, and/or cis/trans isomerism and leads to clear impurity peaks on HPLC.
The present inventors seek a process for the manufacture of a polyunsaturated ester or thioester and eventually a corresponding polyunsaturated ketone that produces, after suitable purification, a pharmaceutical grade compound with minimal oxidation and cis/trans isomerization by products.